TY - JOUR
T1 - In vitro metabolic formation of a new metabolite, 6β-hydroxymethyl-Δ9- tetrahydrocannabinol from cannabidiol through an epoxide intermediate and its pharmacological effects on mice
AU - Nagai, K.
AU - Watanabe, K.
AU - Narimatsu, S.
AU - Gohda, H.
AU - Matsunaga, T.
AU - Yamamoto, I.
AU - Yoshimura, H.
PY - 1993
Y1 - 1993
N2 - The oxidative metabolism of cannabidiol (CBD) at the 8,9-double bond was examined. 8R,9-Epoxy-CBD was identified by GC-MS as a new metabolite of CBD produced by hepatic microsomal fractions of guinea pigs, rats and mice. The reaction required NADPH as a cofactor and molecular oxygen. The optimal pH for the reaction was 7.4-8.0. The 8R,9-epoxy-CBD forming activity was highest in guinea pigs, followed by mice and rats in the presence of 3,3.3- trichloropropene-1,2-oxide (TCPO), an inhibitor of epoxide hydrolase. The activity was significantly suppressed by SKF 525-A, σ-naphthoflavone, metyrapone and carbon monoxide. 8R,9-Epoxy-CBD was further converted to 6β- hydroxymethyl-Δ9-tetrahydrocannabinol (6β-CH2OH-Δ9-THC) and 8,9- dihydro-8,9-dihydroxy-CBD by hepatic microsomes of guinea pigs, rats and mice. Microsomal formation of 6β-CH2OH-Δ9-THC was markedly increased in the presence of TCPO with a concomitant decrease in the formation of 8,9- dihydro-8,9-dihydroxy-CBD in all animal species examined. Furthermore, 6β- CH2OH-Δ9-THC was also identified as a new metabolite of CBD produced by hepatic microsomes of guinea pigs. 6β-CH2OH-Δ9-THC exhibited THC-like pharmacological effects, catalepsy, analgesia, pentobarbital-induced sleep prolongation and hypothermia in mice, although these effects were less marked than those of Δ9-THC. This study presents the first example of the biotransformation of CBD to a Δ9-THC derivative which exhibits some pharmacological effects.
AB - The oxidative metabolism of cannabidiol (CBD) at the 8,9-double bond was examined. 8R,9-Epoxy-CBD was identified by GC-MS as a new metabolite of CBD produced by hepatic microsomal fractions of guinea pigs, rats and mice. The reaction required NADPH as a cofactor and molecular oxygen. The optimal pH for the reaction was 7.4-8.0. The 8R,9-epoxy-CBD forming activity was highest in guinea pigs, followed by mice and rats in the presence of 3,3.3- trichloropropene-1,2-oxide (TCPO), an inhibitor of epoxide hydrolase. The activity was significantly suppressed by SKF 525-A, σ-naphthoflavone, metyrapone and carbon monoxide. 8R,9-Epoxy-CBD was further converted to 6β- hydroxymethyl-Δ9-tetrahydrocannabinol (6β-CH2OH-Δ9-THC) and 8,9- dihydro-8,9-dihydroxy-CBD by hepatic microsomes of guinea pigs, rats and mice. Microsomal formation of 6β-CH2OH-Δ9-THC was markedly increased in the presence of TCPO with a concomitant decrease in the formation of 8,9- dihydro-8,9-dihydroxy-CBD in all animal species examined. Furthermore, 6β- CH2OH-Δ9-THC was also identified as a new metabolite of CBD produced by hepatic microsomes of guinea pigs. 6β-CH2OH-Δ9-THC exhibited THC-like pharmacological effects, catalepsy, analgesia, pentobarbital-induced sleep prolongation and hypothermia in mice, although these effects were less marked than those of Δ9-THC. This study presents the first example of the biotransformation of CBD to a Δ9-THC derivative which exhibits some pharmacological effects.
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M3 - Article
C2 - 8287029
AN - SCOPUS:0027485871
SN - 0918-6158
VL - 16
SP - 1008
EP - 1013
JO - Biological and Pharmaceutical Bulletin
JF - Biological and Pharmaceutical Bulletin
IS - 10
ER -